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May 1997
Concomitant Endothelin Receptor Subtype-A Blockade During the Progression of Pacing-Induced Congestive Heart Failure in Rabbits.
Spinale FG, Walker JD, Mukherjee R, Iannini JP, Keever AT, Gallagher KP; Circulation 1997; 95:1918-29.
[ see abstract below ]
A primary goal in anesthesiology/critical care medicine is control of cardiopulmonary function. Many of the drugs currently deployed by practitioners in this regard are related to knowledge acquired over several decades about "Classic" physiological mediators. Although a number of "novel" mediators have been identified in recent years, relatively little has surfaced using this new information which provides additional therapeutic avenues in cardiopulmonary disorders of major clinical signification.
The two articles reviewed here may reveal major new additions to the therapy of congestive heart failure and asthma, reflecting advances in applications related to endothelin (ET-1) and the leukotrienes, respectively. Clinicians who view themselves as experts in applied pharmacology should be aware of these emerging therapeutic groups.
Endothelin is an endogenously synthesized, 21-amino acid peptide with diverse biological activities, including: (a) profound and prolonged vasoconstrictor effects on both venous and arterial smooth muscle; (b) positive inotropic and chronotropic effects on myocardial cells; (c) proliferative effects on a variety of cell types; (d) stimulation of hormone release; (e) modulation of CNS activities; (f) perhaps an important role in normal morphogenesis; and (g) likely involved as an autocrine factor in cardiac hypertrophy.
Presently, a large number of studies have reported that endothelin plasma levels are increased in patients who are symptomatic with congestive heart failure (CHF). Additionally, studies have shown that ET-1 receptor antagonists reduce cardiovascular hemodynamic parameters as well as cardiac index, thus providing a beneficial effect in patients with CHF. This article took these general observations a step further by examining the effectiveness of chronic blockade of the ETA receptor, looking not only at global left ventricular function, but also cardiac myocytes taken from these treated animals.
In doing this more extensive study, the authors have provided the first evidence of the beneficial effects ET-1 receptor blockade on left ventricular function at the cellular level. Although a variety of mechanisms of action of the beneficial effects of ET-1 in CHF have been proposed by the authors, the predominant interpretation presently is based on the fact that CHF is a syndrome characterized by marked activation of neuromuscular mediators. The ET-1 system may be considered a possible additional factor in this syndrome and therefor offers another therapeutic approach to join with the sympathetic nervous system and the renin-angiotensin system.
This study adds strong support for the view that, analogous to the renin-angiotensin system, the ET-1 system is a mechanism used during CHF which attempts compensate for decreased left ventricular function. The release of ET-1, a potent vasoconstrictor substance, under these conditions may actually contribute to the overload of the heart, thereby further hastening the deterioration of LV function. These results further emphasize the therapeutic potential for ET-1 receptor blockade in the setting of CHF. A number of specific ET-1 receptor antagonists, including oral dosage forms are in the drug-development pipeline and can be expected to enter clinical trials in the relatively near future.
Return to the Current Literature Review Front Page, or read the abstract:
ABSTRACT
Background: Plasma levels of ehdothelin-1 (ET-1) are increased in patients and animals with severe congestive heart failure (CHF). It remains unknown, however, whether ET-1 plays a direct and contributory role in the progression of CHF. Accordingly, the present process tested the hypothesis that chronic blockade of the ETA receptor would have direct and beneficial effects on left ventricular (LV) and myocyte function in a model of CHF.
Methods and Results: Global LV and isolated myocyte function were examined in rabbits in the following groups (12 per group): chronic rapid ventricular pacing (RVP; 400bpm. 3 weeks), RVP and concomitant administration of the selective ETA receptor antagonist (PD 156707 24 mg/d), and sham controls. LV fractional shortening decreased after RVP (17 +/- 5 versus 42 +/- 3%) and end-diastolie dimension increased (2.36 +/- 0.44 versus 1.24 +/- 0.18 cm) compared with controls (P less than .05). With RVP plus ETA blockade, LV fractional shortening was increased (33 +/- 6%) and end-diastolie dimension decreased (2.02 +/- 0.30 cm) compared with RVP-only values (P less than .05).
Plasma norepinephrine and endothelin increased twofold in the RVP group. In the RVP plus ETA blockade group, plasma endothelin increased threefold compared with RVP values. Isolated myocyte shortening velocity declined after RVP (42 +/- 13 versus 72 +/- 10 um/s, P less than.05) compared with controls but was normalized with RVP plus ETA blockade (77 +/- 16 um/s). Myocyte inotropic response to extracellular Ca21, Beta-receptor stimulation, and ET-1 was reduced in the RVP group and returned to control levels with RVP and concomitant ETA receptor blockade.
Conclusions: The results from this study suggest that chronically elevated ET-1 levels and subsequent activation of the ETA receptor plays a direct and contributory role in the progression of the CHF process. Thus, specific ETA receptor blockade may provide a new and useful therapeutic modality in the setting of CHF.
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